This invention relates to the use of xanthines as immune suppressants in mammals. In one embodiment of the invention the xanthines suppress the activation of lymphocytes in mammals. In another embodiment, this invention relates to the use of xanthines to inhibit the effects associated with autoimmune disease in humans.
The immune system of vertebrates protects them from disease-causing (pathogenic) microorganisms, such as bacteria and viruses, from parasites, and from cancer cells. The immune system specifically recognizes and selectively eliminates foreign invaders by a process known as the immune response.
The immune system has evolved to provide an organism that can respond specifically to a wide variety of antigens. In order for an immune response to occur following antigen challenge, antigen must not only be recognized by antigen specific lymphocytes, but this recognition event must lead to a variety of cellular responses. T lymphocytes, together with B lymphocytes, represent the two antigen specific components of the cellular immune system. The activation of resting T lymphocytes is critical to most immune responses, because cellular activation allows the cells to exert their regulatory or effector activities. During activation relatively quiescent cells undergo complex changes involving cell differentiation and proliferation.
The immune response that results in the neutralization and elimination of foreign invaders may also cause disease. Diseases involving the immune system can be grouped into two general classes. Deficiency diseases result when a component of the system fails to function. These diseases manifest themselves clinically by low resistance to infection and loss of immunologic surveillance functions. Hypersensitivity diseases result when the system reacts under inappropriate conditions. For example, immune responses to self components may lead to a breakdown in immunological tolerance causing autoimmune diseases. An autoimmune disease is one in which the body makes an immune response to one of its own constituent antigens, which then causes pathologic damage. A multiplicity of organs and tissues is involved in autoimmune disease. Autoimmunity is a major problem in clinical medicine and is the cause of great economic loss.
There exists a need in the art for means for controlling the immune response by suppressing the immune system in mammals. There also exists a need for the clinical management of hypersensitivity diseases, including autoimmune diseases in humans. Because the existing treatments and means for preventing autoimmune diseases are not entirely satisfactory, new approaches in preventing or treating such diseases must be found, since autoimmune diseases is a major cause of suffering in patients afflicted with immune response disorders.
This invention aids in fulfilling these needs in the art by providing a method of suppressing the activation of lymphocytes, including T lymphocytes and B lymphocytes, in mammals, such as humans. More particularly, this invention provides a method of suppressing activation of lymphocytes in a mammal by administering to the human at least one 7-(oxoalkyl) 1,3-dialkyl xanthine, other than denbufylline, of the formula: 
in which
R1 and R2 are the same or different and are independently selected from the group consisting of straight-chain or branched-chain alkyl radicals with 2 to 6 carbon atoms, cyclohexyl, straight chain or branched chain alkoxyalkyl, and hydroxyalkyl radicals; and
A is a hydrocarbon radical with up to 4 carbon atoms which can be substituted by a methyl group.
The xanthine of formula (I) is employed in an amount that is effective in suppressing lymphocyte activation.
This invention also provides a method of suppressing lymphocyte activation in a mammal, comprising administering to the mammal a compound of the formula: 
wherein at least one of R1 and R3 is either
(a) a branched hydroxyalkyl group of the formula 
xe2x80x83with a tertiary alcohol function, in which R4 stands for an alkyl group with 1 to 3 carbon atoms and n stands for a whole number from 2 to 5, the other R1 or R3 group that may optionally be present stands for a hydrogen atom or an aliphatic hydrocarbon group R5 with up to 6 carbon atoms, whose carbon chain may be interrupted by up to 2 oxygen atoms or may be substituted with a hydroxy or oxo group, or
(b) at least one of R1 or R3 is an oxoallyl group of the formula 
wherein R6 is C1-C6 alkyl, and p 2, 3 or 4; the other R1 or R3 being defined as above and R2 represents an alkyl group with 1 to 4 carbon atoms.
The xanthine of formula (II) is employed in an amount that is effective in suppressing lymphocyte activation. The well known pharmaceutical pentoxifylline is an example of a compound within the general formula (II). Pentoxifylline (xe2x80x9cPTXXxe2x80x9d) is commercially available under the trademark Trentals in the form of tablets for oral administration. Although this compound has been used for time as a pharmaceutical to improve the flow properties of blood (clinical trials in 1971), it has not been reported effective as an inhibitor of lymphocyte activation.